During the late stage, 20-30% of patients with breast cancer develop brain metastasis and the one year survival rate of these patients is less than 20%. Therefore, it is of paramount importance to elucidate the molecular mechanism involved in the metastatic process in order to define a specific therapeutic target. Long non-coding RNAs (lncRNAs) that are distinguished from other small RNAs have recently drawn strong attention for their critical roles in tumor progression. We have examined the expression profile of lncRNAs in tumor tissues from primary and brain-metastatic lesions of breast cancer patients using our newly constructed lncRNA library. We found that (i) brain metastatic lesions express significantly lower amount of the lncRNA, XIST, which is linked to the X chromosome and plays a critical role in the X chromosome inactivation, (ii) when XIST was silenced in breast cancer cells, such cells significantly promoted brain metastatic growth in mice, and (iii) XIST expression presented a significant reverse correlation with brain but not with bone metastasis in patients. Therefore, we hypothesize that the loss of XIST promotes brain metastasis of breast cancer by stimulating EMT and self-renewal of tumor initiating cells through activation of the PLS3 and c-met pathways in the brain microenvironment. We also hypothesize that PTER suppresses metastatic ability of tumor initiating cells by blocking the c-Met pathway. To test these hypotheses, we will elucidate the molecular pathway through which loss of XIST stimulates the EMT by activating PLS3 on the X-chromosome (Aim 1). We will also decipher the mechanism by which the loss of XIST activates the c-Met pathway thereby promoting stemness of the metastasis initiating cells (Aim 2). Finally, we will test the efficacy of PTER or cabozantinib on metastasis initiating cells using xenograft, PDX and genetic mouse models (Aim 3). We believe that the outcome of our study will provide a paradigm shift in our current understanding of the pathology of brain metastasis and also have a significant impact on the future treatment of this devastating disease. The results of this study will significantly impact on this research field in three ways. First, we found that XIST plays a pivotal role in metastasis initiating cells in brain metastasis of breast cancer. XIST is known for its critical function for X inactivation and for modulation of pluripotency of embryonic stem cells; however, how this lncRNA is involved in tumor progression is virtually unknown. Therefore, the results of this project will reveal a novel pathological mechanism of tumor metastasis and provide a paradigm shift in our understanding of breast cancer progression. Secondly, we propose to decipher the pathway of reciprocal communication between metastasis initiating cells and astrocytes in the brain microenvironment and their roles in the metastatic progression, which we believe, will lead to a discovery of a novel therapeutic target. Finally, we will examine the potential utility of the natural compound, PTER, as a preventive and therapeutic measure for brain metastasis. We will also explore a possibility of PTER as a sensitizer of radiation therapy for the metastatic disease.